Tropolone derivative

ABSTRACT

Tropolone derivatives represented by the formula (I), which have retinoid actions and are useful as active ingredients of medicaments [R 1  to R 4  represent hydrogen atom, an alkyl group, or an alkoxyl group; the ring represented by Ar represents an aryl ring or a heteroaryl ring; X represents a single bond, —N═N—, —CON(R 5 )—, —(C═C) n CON(R 6 )—, —N(R 7 )CON(R 8 )—, —SO 2 N(R 9 )—, —N(R 10 )— (R 5  to R 9  represent hydrogen atom or an alkyl group, n represents 1 to 3, R 10  represents hydrogen atom, an alkyl group, or an acyl group), an alkylene group, an aryldiyl group, or a heterocyclic diyl group; Y represents hydrogen atom, —OR 11  (R 11  represents hydrogen atom, an alkyl group, or an acyl group), —NHR 12  (R 12  represents hydrogen atom, an alkyl group, an acyl group, or amino group), or a halogen atom.

TECHNICAL FIELD

[0001] The present invention relates to tropolone derivatives havingretinoid actions and useful as active ingredients of medicaments.

BACKGROUND ART

[0002] Retinoic acid (vitamin A acid), an active metabolite of vitaminA, has extremely important physiological functions, e.g., inducingdifferentiation of immature cells under development processes towardmature cells having specific functions, enhancement of cellproliferation, and life support action. It has been revealed thatvarious vitamin A derivatives synthesized so far also have similarphysiological functions, for example, the benzoic acid derivativesdisclosed in Japanese Patent Unexamined Publication (KOKAI) Nos.(Sho)61-22047/1986 and (Sho)61-76440/1986, and the compounds describedin Journal of Medicinal Chemistry, 1988, Vol. 31, No. 11, p.2182.“Retinoids” is a general term for retinoic acid and the aforementionedcompounds having retinoic acid-like biological activities.

[0003] For example, it was proved that all-trans retinoic acid binds asa ligand to the retinoic acid receptor (RAR) present in cellularnucleus, which belongs to the intranuclear receptor super family (Evans,R. M., Science, 240, p.889, 1988), and regulates proliferation anddifferentiation of animal cells or cellular mortalities (Petkovich, M.,et al., Nature, 330, pp.444-450, 1987). It has also been suggested thatthe aforementioned compounds having the retinoic acid-like biologicalactivities, e.g.,4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)carbamoyl]benzoicacid: Am80, also bind to RAR in similar manners to retinoic acid toexhibit their physiological actions (see, Hashimoto, Y., Cell Struct.Funct., 16, pp.113-123, 1991; Hashimoto, Y., et al., Biochem. Biophys.Res. Commun., 166, pp.1300-1307, 1990).

[0004] Clinically, these compounds were found to be useful fortherapeutic and preventive treatments of vitamin A deficiency disease,hyperkeratosis of epithelial tissue, rheumatism, delayed allergy, bonediseases, leukemia and certain types of cancer. However, because ofvariety of biological activities of these retinoids, they are not fullysatisfactory medicaments from a viewpoint of side effect. Therefore, ithas been desired to create retinoids having characteristic activities.

DISCLOSURE OF THE INVENTION

[0005] An object of the present invention is to provide novel compoundshaving retinoid actions and useful as active ingredients of medicaments.It has conventionally been considered that a partial structure ofp-substituted benzoic acid (and carboxylic acid having an aromatic6-membered ring of a structure similar thereto) is essential foractivity expression of compounds having potent retinoid actions such asAm80. In order to achieve the foregoing object, the inventor of thepresent invention conducted various researches for novel compoundshaving no carboxyl group. As a result, the inventor found that thetropolone derivatives represented by the following general formula haddesired retinoid actions. The present invention was achieved on thebasis of the above finding.

[0006] The present invention thus provides compounds represented by thefollowing general formula (I):

[0007] wherein, R¹, R², R³ and R⁴ independently represent hydrogen atom,a C₁₋₁₀ alkyl group (said alkyl group may be substituted), or a C₁₋₆alkoxyl group, and when R² and R³ are adjacent to each other, they maycombine together with carbon atoms of the phenyl group to which R² andR³ bind to form a 5- or 6-membered ring (said ring may have one or moreC₁₋₄ alkyl groups or one condensed benzene ring which may have one ormore substituents on the ring); the ring represented by Ar represents anaryl ring or a heteroaryl ring; X represents a single bond, —N═N—,—CON(R⁵)— (wherein R⁵ represents hydrogen atom or a C₁₋₆ alkyl group),—(C═C)_(n)CON(R⁶)— (wherein n represents an integer of 1 to 3, and R⁶represents hydrogen atom or a C₁₋₆ alkyl group), —N(R⁷)CON(R⁸)— (R⁷ andR⁸ represent hydrogen atom or a C₁₋₆ alkyl group), —SO₂N(R⁹)— (R⁹represents hydrogen atom or a C₁₋₆ alkyl group), —N(R¹⁰)— (R¹⁰represents hydrogen atom, a C₁₋₆ alkyl group, or a C₁₋₆ acyl group), aC₁₋₆ alkylene group (said alkylene group may contain one or moreunsaturated bonds or a cyclic structure), an aryldiyl group, or aheterocyclic diyl group; Y represents hydrogen atom, —OR¹¹ (R¹¹represents hydrogen atom, a C₁₋₆ alkyl group, or a C₁₋₆ acyl group),—NHR¹² (R¹² represents hydrogen atom, a C₁₋₆ alkyl group, a C₁₋₆ acylgroup, or amino group), or a halogen atom, or salts thereof. Accordingto a preferred embodiment of the aforementioned invention, the compoundsor the salts thereof, wherein R⁴ is hydrogen atom or a C₁₋₆ alkyl group,Y is hydrogen atom, hydroxyl group, a C₁₋₆ alkoxyl group, hydrazinogroup, or a halogen atom are provided.

[0008] From another aspect, the present invention provides medicamentscomprising the compounds represented by the aforementioned generalformula (I) or physiologically acceptable salts thereof. Thesemedicaments can be used as agents for suppressing action of aphysiologically active substance which binds to an intranuclear receptorbelonging to the intranuclear receptor super family to exhibit thephysiological action.

[0009] The present invention further provides use of the compoundsrepresented by the aforementioned general formula (I) or physiologicallyacceptable salts thereof for manufacture of the aforementionedmedicaments, and methods for suppressing action of a physiologicallyactive substance which binds to an intranuclear receptor belonging tothe intranuclear receptor super family to exhibit the physiologicalaction, which comprises the step of administering an effective amount ofthe compounds represented by the aforementioned general formula (I) orphysiologically acceptable salts thereof to a mammal including human.

BEST MODE FOR CARRYING OUT THE INVENTION

[0010] In the present specification, the alkyl group may be a linear,branched or cyclic alkyl group, or an alkyl group consisting of acombination thereof. Alkyl moieties of the other substituents having thealkyl moiety (an alkoxyl group and the like) have the same meaning. Thehalogen atom referred to herein may be any of fluorine atom, chlorineatom, bromine atom, and iodine atom.

[0011] The groups represented by R¹, R², R³ and R⁴ may bind at anarbitrary position on the ring. As for the C₁₋₁₀ alkyl group representedby R¹, R², R³ and R⁴, examples of the alkyl group include, for example,methyl group, ethyl group, propyl group, isopropyl group, butyl group,isobutyl group, sec-butyl group, tert-butyl group, pentyl group,isopentyl group, neopentyl group, hexyl group, heptyl group, octylgroup, nonyl group, decyl group and the like. When the alkyl grouprepresented by R¹, R², R³ and R⁴ has a substituent, the type of thesubstituent is not particularly limited. However, a halogen atom, morepreferably fluorine atom and the like can be used as the substituent.When R² and R³ combine together with carbon atoms of the phenyl group towhich R² and R³ bind to form a 5- or 6-membered ring, the formed ring ispreferably a 6-membered ring. When the ring has a C₁₋₄ alkyl group onthe ring, methyl group is preferred as the alkyl group. Two to fourmethyl groups, for example, may exist on the ring.

[0012] The aryl group represented by Ar may be a monocyclic aryl groupor a condensed aryl group, and a 6- to 14-membered aryl group can beused. More specifically, examples include, for example, phenyl group,naphthyl group, anthryl group, pyrenyl group and the like. Aryl moietiesof other substituents having the aryl moieties have the same meaning.The aryl group represented by Ar is preferably a monocyclic aryl group,and most preferably phenyl group.

[0013] Type and number of heteroatoms contained in the heteroaryl grouprepresented by Ar are not particularly limited. A heteroaryl groupcontaining one or more heteroatoms selected from the group consisting ofnitrogen atom, oxygen atom and sulfur atom as ring-constituting atoms ispreferred. When two or more heteroatoms are contained, they may be thesame or different. The heteroaryl group may be a monocyclic heteroarylgroup or a condensed heteroaryl group. More specifically, examplesinclude, for example, pyridyl group, pyrimidinyl group, pyrazinyl group,pyridazinyl group, triazinyl group, quinolyl group, isoquinolyl group,quinazolinyl group, phthalazinyl group, quinoxalinyl group,naphthylidinyl group, cinnolinyl group, thienyl group, furyl group,pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group,tetrazolyl group, oxazolyl group, thiazolyl group, thiadiazolyl group,benzothienyl group, benzofuryl group, indolyl group, indazolyl group,benzimidazolyl group, benzotriazolyl group, benzoxazolyl group,benzothiazolyl group, purinyl group and the like. Among them,benzothienyl group is preferred.

[0014] When X represents a single bond, the tropolone ring and the arylring or heteroaryl ring represented by Ar are directly bound to eachother without atom or group. When X represents —CON(R⁵)—, R⁵ ispreferably hydrogen atom. When X represents —(C═C)_(n)CON(R⁶)—, n ispreferably 1 or 2, and R⁶ is preferably hydrogen atom. When X represents—N(R⁷)CON(R⁸)—, R⁷ and R⁸ are preferably hydrogen atoms. When Xrepresents —SO₂N(R⁹)—, R⁹ is preferably hydrogen atom. When X represents—N(R¹⁰)—, R¹⁰ is preferably hydrogen atom or a C₁₋₆ alkyl group, morepreferably hydrogen atom or methyl group. When X represents a C₁₋₆alkylene group, the alkylene group may be linear or branched. When thisalkylene group contains an unsaturated bond, the unsaturated bond may beeither a double bond or a triple bond, or a combination of the both. Thealkylene group preferably contains one triple bond.

[0015] When X represents an aryldiyl group, the aryl ring constitutingthe aryldiyl group may be either a monocyclic aryl ring or a condensedaryl ring, and an aryldiyl group comprising a 6- to 14-membered arylring can be used. More specifically, examples of the aryldiyl groupinclude, for example, phenylene group, naphthyldiyl group, anthryldiylgroup and the like.

[0016] When X represents a heterocyclic diyl group, the heterocyclicring constituting the heterocyclic diyl group may be a monocyclicheterocyclic group or a condensed heterocyclic group. A 5- or 6-memberedmonocyclic heterocyclic ring is preferred. The heterocyclic ring may beany of saturated, partially saturated and aromatic heterocyclic rings.Type and number of heteroatoms contained in the heterocyclic ring arenot particularly limited. A heterocyclic group preferably contains oneor more heteroatoms selected from the group consisting of nitrogen atom,oxygen atom and sulfur atom as ring-constituting atoms. When two or moreheteroatoms are contained, they may be identical or different. Examplesof heterocyclic ring constituting the heterocyclic diyl group includepyrrolidinediyl group, piperazinediyl group, morpholinediyl group,tetrahydrofurandiyl group, dihydropyrandiyl group, pyridinediyl group,pyrimidinediyl group, pyrazinediyl group, pyridazinediyl group,triazinediyl group, quinolinediyl group, isoquinolinediyl group,quinazolinediyl group, phthalazinediyl group, quinoxalinediyl group,naphthylidinediyl group, cinnolinediyl group, thiophenediyl group,furandiyl group, pyrrolediyl group, pyrrolinediyl group, imidazolediylgroup, pyrazolediyl group, triazolediyl group, tetrazolediyl group,oxazolediyl group, thiazolediyl group, thiadiazolediyl group,benzothiophenediyl group, benzofurandiyl group, indolediyl group,indazolediyl group, benzimidazolediyl group, benzotriazolediyl group,benzoxazolediyl group, benzothiazolediyl group, purinediyl group and thelike.

[0017] When Y represents —OR¹¹, R¹¹ is preferably hydrogen atom or aC₁₋₆ alkyl group, more preferably hydrogen atom or methyl group. When Yrepresents —NHR¹², R¹² is preferably amino group. In the aforementionedgeneral formula (I), R⁴ is preferably hydrogen atom or a C₁₋₆ alkylgroup, and Y is preferably hydrogen atom, hydroxyl group, a C₁₋₆ alkoxylgroup, hydrazino group or a halogen atom.

[0018] The compounds of the present invention represented by the generalformula (I) may exist in the forms of acid addition salts or baseaddition salts, and any of such salts also fall within the scope of thecompounds of the present invention. Examples of the acid addition saltsinclude mineral acid salts such as hydrochloride or hydrobromide, andorganic acid salts such as p-toluenesulfonate, methanesulfonate,oxalate, or tartrate. As the base addition salts, metal salts such as,for example, sodium salt, potassium salt, magnesium salt, or calciumsalt, ammonium salts, or organic amine salts such as triethylamine saltor ethanolamine salt may be used. Further, the compounds may exist inthe forms of amino acid salts such as glycine salt. Furthermore, thecompounds of the present invention and salts thereof may also exist ashydrates or solvates, and these substances also fall within the scope ofthe present invention.

[0019] The compounds of the present invention may have one or moreasymmetric carbon atoms depending on types of substituents. Anystereoisomers such as optical isomers and diastereomers, any mixtures ofthe stereoisomers, racemates and the like all fall within the scope ofthe present invention. Further, geometric isomers based on an olefinicdouble bond (syn- or anti-isomer) and any mixtures thereof as well astautomers, if exist, also all fall within the scope of the presentinvention.

[0020] The following compounds are preferred compounds among thecompounds of the present invention represented by the aforementionedgeneral formula (I). However, the compounds of the present invention arenot limited to these compounds. TABLE 1

R¹ R¹⁰ Tp10 H H Tp20 Me H Tp22 Me Me

X Tp30 —NHCONH— Tp40 —SO₂NH— Tp150 —CH₂CH₂— Tp180 -para-Ph— Tp190-meta-Ph—

R¹ R⁵ Tp80 H H Tp82 H Me Tp84 Me H

R X Tp50 tert-Bu —CONH— Tp60 CF₃ —CONH— Tp155 tert-Bu —C≡C— Tp170tert-Bu —N═N—

n Y Tp90 1 OH Tp93 1 Cl Tp95 2 OH

R¹ Y Tp140 H OH Tp141 H OMe Tp145 Me OH Tp146 H NH₂NH₂ Tp149 H H

R⁴ Tp160 H Tp175 isoPr

Z Tp200 O Tp210 S

Z Tp250 —CH═CH— Tp260 S

[0021] Methods for preparation of the aforementioned preferred compoundsencompasses within the compounds of the formula (I) are specificallydescribed in the examples given in the present specification. Therefore,any compounds falling within the scope of the present invention can beprepared by suitably selecting starting materials, regents, reactionconditions and the like used in those preparation methods, and ifnecessary, appropriately modifying or altering the preparation methods.However, the preparation methods of the compounds of the presentinvention are not limited to those specifically explained in theexamples.

[0022] The compounds represented by the aforementioned general formula(I) and salts thereof have retinoid-like physiological activities(typical examples include cell differentiation activity, cellproliferation enhancing activity, life supporting activity and the like)and an action of controlling physiological activities of retinoids.Further, the compounds and salts thereof have an action of suppressingphysiological activities of substances that bind to receptors belongingto the intranuclear receptor super family present in cellular nuclei toexhibit their physiological activities (e.g., steroid compounds, vitaminD compounds including vitamin D₃, thyroxine and the like). Further, theycan also suppress actions of orphan receptors which exist in nuclei andwhose ligands are unknown.

[0023] Therefore, the medicaments comprising the compounds representedby general formula (I) or physiologically acceptable salts thereof asactive ingredients are useful as agents having retinoid-like activities.The medicaments of the present invention comprising the aforementionedcompounds as active ingredients have, for example, cell differentiationactivity, cell proliferation enhancing activity, life supportingactivity and the like, and they can be used as active ingredients ofmedicaments for preventive or therapeutic treatments of vitamin Adeficiency disease, hyperkeratosis of epithelial tissue, psoriasis,allergic diseases, immunological diseases such as rheumatism, bonediseases, diabetes mellitus, leukemia, or cancers.

[0024] The medicament of the present invention comprises, as an activeingredient, one or more kinds of substances selected from the groupconsisting of the compounds represented by the aforementioned generalformula (I) and salts thereof, and hydrates thereof and solvatesthereof. As the medicament of the present invention, the aforementionedsubstance, per se, may be administered. A pharmaceutical composition fororal administration or parenteral administration may preferably beadministered which can be prepared by a method well known to thoseskilled in the art. Examples of the pharmaceutical compositions suitablefor oral administrations include, for example, tablets, capsules,powders, subtilized granules, granules, liquids, syrups and the like.Examples of the pharmaceutical compositions suitable for parenteraladministrations include, for example, injections, drops, suppositories,inhalants, eye drops, nasal drops, ointments, creams, patches,transdermal preparations, transmucosal preparations and the like.

[0025] Examples of pharmaceutically acceptable additives used forpreparation of the aforementioned pharmaceutical compositions include,for example, excipients, disintegrators and disintegrating aids,binders, lubricants, coating agents, colorants, diluents, basematerials, dissolving agents and dissolving aids, isotonic agents, pHmodifiers, stabilizers, propellants, adhesives and the like. They can besuitably selected by those skilled in the art depending on the form ofthe pharmaceutical composition, and two or more kinds of them may beused in combination. The aforementioned pharmaceutical composition maybe further added with one or more kinds of active ingredients such asretinoids and steroid compounds and used as a pharmaceutical compositionin the form of so-called combined medicament. The pharmaceuticalcomposition can be prepared in the form either for oral administrationor parenteral administration.

EXAMPLES

[0026] The present invention will be more specifically explained withreference to the following examples. However, the scope of the presentinvention is not limited to these examples. The compound numbers in theexamples correspond to those of the compounds described above aspreferred examples.

Example 1 Synthesis of Compound Tp05

[0027]

[0028] Tropolone (4.54 g, 37.2 mmol) was dissolved in acetic acid (12ml) and water (4 ml) and gradually added with sodium nitrite (3.72 g,53.9 mmol) dissolved in water (8 ml) under ice cooling. After 1 hour,the reaction solution was added with water, and the crystals werecollected by filtration, then sufficiently washed with water, washedwith a small amount of methanol and dried to obtain a crude product ofCompound I-1 (5.03 g, 90%). Compound I-1: ¹H-NMR (400 MHz, DMSO-d₆, 30°C.) 13.92 (s, 1 H), 7.70 (d, J=12.4 Hz, 1 H), 7.22 (d, J=11.7 Hz, 1 H),6.56 (d, J=12.8 Hz, 2 H)

[0029] Compound I-1 (5.00 g, 33.1 mmol) was suspended in methanol (50ml) and added with PtO₂ (40 mg) to perform catalytic hydrogen reduction.After 2.5 hours, the reaction was terminated, and the reaction solutionwas added with activated carbon (500 mg) and filtered through Cerite,and the filtrate was concentrated to obtain a crude product of CompoundI-2 (4.30 g, 95%). Compound 1-2: ¹H-NMR (400 MHz, DMSO-d₆, 30° C.) 7.10(dd, J=10.6, 1.3 Hz, 2 H), 6.71 (dd, J=10.6, 1.3 Hz, 2 H), 6.23 (s, 2 H)

[0030] Compound I-2 (1.99 g, 14.5 mmol) was suspended in water (50 ml)and concentrated sulfuric acid (22.4 ml) and gradually added with asolution of sodium nitrite (1.20 g, 17.4 mmol) dissolved in water (5ml). After stirring for 30 minutes, the reaction solution was refluxedfor 2 hours. Then, the reaction solution was cooled, added with waterand extracted with ethyl acetate, and the organic layer was washed withsaturated brine, dehydrated over MgSO₄ and then concentrated to obtain acrude product of Compound I-3 (836 mg, 42%). Compound I-3: ¹H-NMR (400MHz, DMSO-d₆, 30° C.) 10.24 (b, 1 H), 7.15 (dt, J=11.7, 1.3 Hz, 2 H),6.96 (dd, J=10.4, 1.5 Hz, 2 H)

[0031] Compound I-3 (420 mg, 3.04 mmol) and 2,6-lutidine (0.85 ml, 782mg, 7.30 mmol, 2.4 Eq) was suspended in methylene chloride (5 ml), addedwith trifluoroacetic anhydride (TFA) (1.89 g, 6.70 mmol) at −30° C. andstirred at room temperature. After 3.5 hours, the reaction solution wasadded with water and extracted with methylene chloride, and the organiclayer was washed with 2 N hydrochloric acid and saturated brine,dehydrated over MgSO₄, and then concentrated. The total crude crystalswere dissolved in methanol (5 ml), added with triethylamine (1 ml) andstirred at room temperature. After 3 hours, the solvent was evaporated,and the residue was purified by silica gel column chromatography (ethylacetate), to obtain Compound I-4 (258 mg, 34%). Compound I-4: ¹H-NMR(400 MHz, DMSO-d₆, 30° C.) 7.45 (dd, J=12.9, 2.9 Hz, 1 H), 7.39 (dd,J=10.7, 2.9 Hz, 1 H), 7.10 (d, J=12.9 Hz, 1 H), 6.93 (d, J=10.7 Hz, 1H), 3.90 (s, 3 H)

[0032] 2-Bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (328mg, 1.23 mmol) was dissolved in tetrahydrofuran (THF, 3 ml), added witha 1.6 M solution of n-BuLi (1.48 mmol) in hexane (0.92 ml) at −78° C.and stirred for 30 minutes. This solution was added to a solution ofzinc chloride (168 mg, 1.23 mmol) dissolved in THF (2 ml) and stirred atroom temperature. After 1 hour, the reaction solution was added to asolution of Compound I-4 (220 mg, 0.82 mmol) and Pd(PPh₃)₄ (71 mg, 0.062mmol) dissolved in THF (5 ml) and stirred at room temperature. After 4hours, the reaction solution was added with water and extracted withethyl acetate, and the organic layer was washed with saturated brine,dehydrated over MgSO₄ and then concentrated. The residue was purified byflash silica gel column chromatography (ethyl acetate:n-hexane=2:1) toobtain Compound I-5 (138 mg, 52%). Compound I-5: ¹H-NMR (400 MHz,DMSO-d₆, 30° C.) 7.55 (dd, 1 H, overlapped with Pd(PPh₃)₄), 7.47 (d,J=2.2 Hz, 1 H), 7.40 (d, J=8.3 Hz, 1 H), 7.37 (dd, J=10.3, 1.7 Hz, 1 H),7.30 (dd, J=8.1, 2.0 Hz, 1 H), 7.11 (d, J=12.7 Hz, 1 H), 7.07 (d, J=10.5Hz, 1 H), 7.07 (d, J=10.5 Hz, 1 H), 3.87 (s, 4 H), 1.66 (s, 4 H), 1.29(s, 6 H), 1.26 (s, 6 H)

[0033] Compound I-5 (130 mg, 0.40 mmol) was dissolved in ethanol (6 ml),added with 2 N sodium hydroxide (3 ml) and stirred at room temperature.After 15 hours, the reaction solution was made acidic with 2 Nhydrochloric acid, extracted with ethyl acetate, washed with saturatedbrine, dehydrated over MgSO₄ and then concentrated. The residue wasrecrystallized from ethanol to obtain Compound Tp05 (38 mg, 31%).Compound Tp05: yellow needle crystals (ethanol); melting point 161° C.;¹H-NMR (400 MHz, DMSO-d₆, 30° C.) 7.64 (d, J=11.7 Hz, 2 H), 4.78 (d,J=2.0 Hz, 1 H), 7.40 (d, J=8.3 Hz, 1 H), 7.30 (dd, J=8.3, 2.0 Hz, 1 H),7.27 (d, J=11.7 Hz, 2 H); Anal. Calcd. for C₂₁H₂₄O₂ C, (81.78%) H,(7.87%) Found C, (81.57%) H, (7.87%)

Example 2 Synthesis of Compound Tp10

[0034]

[0035] Compound I-2 (5.38 g, 39.3 mmol) was suspended in concentratedhydrochloric acid (21 ml) and added with ice (30 g). The reactionsolution was gradually added with sodium nitrite (2.98 g, 43.2 mmol)dissolved in water (15 ml) at 0° C. and stirred for further 30 minutes.The reaction solution was returned to room temperature and graduallyadded with a solution of potassium iodide (71.7 g, 432 mmol) dissolvedin water (90 ml) and the mixture was left with stirring overnight. Thereaction solution was added with ethyl acetate, and the insoluble solidswere removed by filtration to obtain a crude product of Compound II-1(3.45 g). The ethyl acetate layer was further washed with saturatedbrine, dehydrated over MgSO₄ and then concentrated to obtain CompoundII-1 (3.45 g, 6.90 g in total, 71%). Compound II-1: ¹H-NMR (400 MHz,DMSO-d₆, 30° C.) 7.83 (d, J=11.9 Hz, 2 H), 6.81 (d, J=11.7 Hz, 2 H)

[0036] Compound II-1 (300 mg, 1.21 mmol) and 2,6-lutidine (0.11 ml, 97mg, 1.45 mmol, 2.4 Eq) were suspended in methylene chloride (3 ml),added with anhydrous TFA (375 mg, 1.33 mmol) −30° C. and stirred at roomtemperature. After 2 hours, the reaction solution was added with waterand extracted with methylene chloride, and the organic layer was washedwith 2 N hydrochloric acid and saturated brine, dehydrated over MgSO₄and then concentrated. The total crude crystals were dissolved inmethanol (4 ml), added with triethylamine (1.5 ml) and stirred at roomtemperature. After 1 hour, the solvent was evaporated, and the residuewas purified by flash silica gel column chromatography (ethylacetate:n-hexane=2:1) to obtain Compound II-2 (135 mg, 43%). CompoundII-2: ¹H-NMR (400 MHz, DMSO-d₆, 30° C.) 7.75 (dd, J=10.3, 1.7 Hz, 1 H),7.63 (dd, J=12.7, 1.7 Hz, 1 H), 6.65 (d, J=12.7 Hz, 1 H), 6.60 (d, J=1.5Hz, 1 H), 3.81 (s, 3 H)

[0037] Compound II-2 (310 mg, 1.18 mmol),2-amino-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (240 mg, 1.18mmol), cesium carbonate (463 mg, 1.42 mmol) and 2.5 mol % Pd₂(dba)₃(27.1 mg, 0.030 mmol) and racemic BINAP (81.0 mg, 0.13 mmol) weresuspended in anhydrous toluene (8 ml) and stirred at 100° C. After 5hours, the reaction solution was cooled to room temperature, added withwater and extracted with ethyl acetate, and the organic layer was washedwith saturated brine, dehydrated over MgSO₄ and then concentrated. Theresidue was purified by flash silica gel column chromatography (ethylacetate:methanol=40:1) to obtain Compound II-3 (98 mg, 19%). CompoundII-3: ¹H-NMR (400 MHz, DMSO-d₆, 30° C.) 8.51 (s, 1 H), 7.27 (d, J=8.5Hz, 1 H), 7.15 (dd, J=13.2, 2.7 Hz, 1 H), 7.02 (d, J=13.0 Hz, 1 H), 6.94(dd, J=8.5, 2.2 Hz, 1 H), 6.93 (d, J=11.5 Hz, 1 H), 6.55 (dd, J=11.2,2.7 Hz, 1 H), 3.71 (s, 3 H), 1.64 (s, 4 H), 1.24 (s, 12 H)

[0038] Compound II-3 (90 mg, 0.27 mmol) was suspended in 47% HBr (5 ml)and refluxed. After 9 hours, the reaction solution was diluted withwater and extracted with ethyl acetate, and the organic layer was washedwith saturated brine, dehydrated over MgSO₄ and then concentrated. Acrude product of Compound Tp10 was obtained (94 mg, quant). CompoundTp10: brown needle crystals (ethanol/water); melting point 216° C.;¹H-NMR (400 MHz, DMSO-d₆, 30° C.) 8.58 (s, 1 H), 7.28 (d, J=8.3 Hz, 1H), 7.16 (dd, J=12.2, 2 H), 7.03 (d, J=11.5 Hz, 2 H), 7.02 (d, J=2.5 Hz,1 H), 6.94 (dd, J=8.5, 2.5 Hz, 1 H), 1.64 (s, 4 H), 1.23 (s, 6 H), 1.23(s, 6 H)

Example 3 Synthesis of Compounds Tp20 and Tp22

[0039]

[0040] Compound II-2 (158 mg, 0.60 mmol),2-amino-5,6,7,8-tetrahydro-3,5,5,8,8-tetramethylnaphthalene (131 mg,0.60 mmol), cesium carbonate (236 mg, 0.72 mmol), 2.5 mol % Pd₂(dba)₃(13.8 mg, 0.015 mmol) and racemic BINAP (41.1 mg, 0.066 mmol) weresuspended in anhydrous toluene (4 ml) and stirred at 100° C. After 5hours, the reaction solution was cooled to room temperature and addedwith water and extracted with ethyl acetate, and the organic layer waswashed with saturated brine, dehydrated over MgSO₄ and thenconcentrated. The residue was purified by flash silica gel columnchromatography (ethyl acetate:methanol=40:1) to obtain Compound III-1(129 mg, 50%). Compound III-1: ¹H-NMR (400 MHz, DMSO-d₆, 30° C.) 8.14(s, 1 H), 7.21 (s, 1 H), 7.11 (dd, J=13.2, 2.2 Hz, 1 H), 7.02 (s, 1 H),7.01 (d, J=13.0 Hz, 1 H), 6.91 (d, J=11.2 Hz, 1 H), 5.91 (dd, J=11.2,2.4 Hz, 1 H), 3.66 (s, 3 H), 2.09 (s, 3 H), 1.63 (s, 4 H), 1.24 (s, 6H), 1.20 (s, 6 H)

[0041] Compound III-1 (125 mg, 0.36 mmol) was suspended in 47% HBr (6ml) and refluxed. After 3 days, the reaction solution was diluted withwater and extracted with ethyl acetate, and the organic layer was washedwith saturated brine, dehydrated over MgSO₄ and then concentrated. Acrude product of Compound Tp20 was obtained (131 mg, quant). CompoundTp20: yellow powder (methylene chloride/n-hexane); melting point 166°C.; ¹H-NMR (400 MHz, DMSO-d₆, 30° C.) 8.28 (s, 1 H), 7.21 (s, 1 H), 7.15(d, J=12.2 Hz, 2 H), 7.04 (s, 1 H), 6.72 (d, J=12.2 Hz, 2 H), 2.09 (s, 1H), 1.63 (s, 4 H), 1.25 (s, 6 H), 1.30 (s, 6 H); Anal. Calcd. forC₂₂H₂₇NO₂.1/4H₂O C, (77.27%) H, (8.11%) N, (4.10%) Found C, (77.37%) H,(8.02%) N, (4.12%)

[0042] NaH (60% in oil, 16 mg, 0.43 mmol) was washed with n-hexane,dried and then suspended in DMF (1 ml). The suspension was added withCompound III-1(100 mg, 0.28 mmol) dissolved in DMF (2 ml) and stirred atroom temperature. After 20 minutes, the reaction solution was added withmethyl iodide (0.1 ml) and stirred at room temperature for 1 hour. Thereaction solution was added with water and extracted with ether, and theorganic layer was washed with saturated brine, dehydrated over MgSO₄ andthen concentrated. The residue was purified by flash silica gel columnchromatography (ethyl acetate:methanol=40:1→20:1) to obtain CompoundIII-2 (70 mg, 48%). Compound III-2: ¹H-NMR (400 MHz, DMSO-d₆, 30° C.)7.28 (s, 1 H), 7.03 (s, 1 H), 7.01 (d, J=11.3 Hz, 1 H), 6.89 (d, J=13.4Hz, 1 H), 6.72 (dd, J=13.4, 2.9 Hz, 1 H), 6.22 (dd, J=11.3, 2.9 Hz, 1H), 3.72 (s, 3 H), 3.18 (s, 3 H), 2.04 (s, 3 H), 1.63 (s, 4 H), 1.26 (s,6 H), 1.19 (s, 6 H)

[0043] Compound III-2 (65 mg, 0.18 mmol) was suspended in 47% HBr (3.5ml) and refluxed. After 24 hours, the reaction solution was diluted withwater and extracted with ethyl acetate, and the organic layer was washedwith saturated brine, dehydrated over MgSO₄ and then concentrated. Acrude product of Compound Tp22 was obtained (66 mg, quant). CompoundTp22: brown needle crystals (ethanol/water); melting point 168° C.;¹H-NMR (400 MHz, DMSO-d₆, 30° C.) 7.29 (s, 1 H), 7.14 (d, J=12.4 Hz, 2H), 7.05 (s, 1 H), 6.65 (d, J=12.5 Hz, 2 H), 3.19 (s, 1 H), 2.03 (s, 3H), 1.64 (s, 4 H), 1.26 (s, 6 H), 1.19 (s, 6 H); Anal. Calcd. forC₂₃H₂₉N₁O₂ C, (78.60%) H, (8.32%) N, (3.98%) Found C, (78.47%) H,(8.41%) N, (3.92%)

Example 4 Synthesis of Compound Tp30

[0044]

[0045] Compound I-2 (250 mg, 2.07 mmol) was suspended in anhydrousmethylene chloride (5 ml), added with tosyl chloride (473 mg, 2.48 mmol)and triethylamine (1 ml) and stirred at room temperature. After 5 hours,the reaction solution was added with water and extracted with ethylacetate, and the organic layer was washed with saturated brine,dehydrated over MgSO₄ and then concentrated. The residue was purified byflash silica gel column chromatography (ethyl acetate) to obtainCompound IV-1 (245 mg, 46%). ¹H-NMR (400 MHz, DMSO-d₆, 30° C.) 7.77 (d,J=8.3 Hz, 2 H), 7.41 (d, J=8.5 Hz, 2 H), 7.22 (s, 2 H), 7.05 (d, J=11.2Hz, 1 H), 6.98 (d, J=13.2 Hz, 1 H), 6.96 (dd, J=13.4, 1.7 Hz, 1 H), 5.92(dd, J=11.2, 2.0 Hz, 1 H), 2.40 (s, 3 H)

[0046] 5,6,7,8-Tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxylicacid (500 mg, 2.16 mmol) was suspended in anhydrous benzene (5 ml) andthionyl chloride (2.56 g) and refluxed. After 2 hours, the solvent wasevaporated, and the residue was dissolved in acetone (5 ml), added withsodium azide (238 mg, 3.66 mmol) dissolved in water (1.2 ml) and stirredat 35 to 40° C. for 30 minutes. The reaction solution was added withwater, and the precipitates were collected by filtration andsufficiently washed with water. A crude product of Compound IV-2 wasobtained (482 mg, 87%). Compound IV-2: ¹H-NMR (400 MHz, DMSO-d₆, 30° C.)7.89 (d, J=2.0 Hz, 1 H), 7.68 (dd, J=8.3, 2.0 Hz, 1 H), 7.51 (d, J=8.3Hz, 1 H), 1.66 (s, 4 H), 1.25 (s, 12 H)

[0047] Compound IV-2 (206 mg, 0.80 mmol) was suspended in anhydroustoluene (3 ml) and refluxed. After 2 hours, the reaction solution wasreturned to room temperature, added with Compound IV-1 (200 mg, 0.69mmol) and dimethylaminopyridine (DMAP, 8.9 mg, 0.072 mmol) and refluxed.After 20 hours, the reaction solution was returned to room temperature,added with water and extracted with ethyl acetate, and after theinsoluble solids were removed by filtration, the organic layer waswashed with saturated brine, dehydrated over MgSO₄ and thenconcentrated. The residue was purified by silica gel columnchromatography (ethyl acetate) to obtain Compound IV-3 (68 mg, 19%).Compound IV-3: ¹H-NMR (400 MHz, DMSO-d₆, 30° C.) 9.27 (s, 1 H), 8.81 (s,1 H), 7.80 (d, J=8.1 Hz, 2 H), 7.50 (dd, J=11.7, 1.9 Hz, 1 H), 7.45 (d,J=8.5 Hz, 2 H), 7.38 (d, J=1.9 Hz, 1 H), 7.37 (dd, J=16.8 , 2.5 Hz, 1H), 7.34 (d, J=11.2 Hz, 1 H), 7.23 (d, J=12.6 Hz, 1 H), 7.16 (dd, J=8.3,1.9 Hz, 1 H), 7.14 (d, J=13.2 Hz, 1 H), 2.42 (s, 3 H), 1.62 (s, 3 H),1.22 (s, 6 H), 1.21 (s, 6 H)

[0048] Compound IV-3 (60 mg, 0.12 mmol) and sodium hydroxide (40 mg)were dissolved in methanol (12 ml) and stirred at room temperature.After 5 hours, the reaction solution was concentrated under reducedpressure at a temperature below 60° C., added with water, and after pHwas made about 4.5 to 5.0 with 2 N hydrochloric acid, extracted withethyl acetate, and the organic layer was washed with water and saturatedbrine, dehydrated over MgSO₄ and then concentrated. The residue waspurified by flash silica gel column chromatography (ethyl acetate) toobtain Compound Tp30 (25 mg, 59%). Compound Tp30: light yellow powder(methanol); melting point 207° C.; ¹H-NMR (400 MHz, DMSO-d₆, 30° C.)8.78 (s, 1 H), 8.59 (s, 1 H), 7.57 (d, J=12.2 Hz, 2 H), 7.37 (d, J=2.2Hz, 1 H), 7.22 (d, J=12.2 Hz, 2 H), 7.20 (d, J=8.6 Hz, 1 H), 7.15 (dd,J=2.2, 8.6 Hz, 1 H), 1.62 (s, 4 H), 1.22 (s, 6 H), 1.21 (s, 6 H); Anal.Calcd. for C₂₂H₂₆N₂O₃.1/2H₂O C, (70.38%) H, (7.25%) N, (7.46%) Found C,(70.32%) H, (7.21%) N, (7.37%)

Example 5 Synthesis of Compound Tp40

[0049]

[0050] Compound I-2 (1.00 g, 7.30 mmol) was suspended in anhydrousmethylene chloride (10 ml), added with triethylamine (1.5 ml) and mesylchloride (836 mg, 0.56 ml, 7.30 mmol) and stirred at room temperature.After 28 hours, the solvent was evaporated, and the residue was purifiedby flash silica gel column chromatography (ethyl acetate) to obtainCompound V-1 (828 mg, 52%). Compound V-1: ¹H-NMR (400 MHz, DMSO-d₆, 30°C.) 7.29 (bs, 2 H), 7.24 (dd, J=12.2, 1.0 Hz, 1 H), 7.13 (d, J=13.2 Hz,1 H), 7.02 (dd, J=13.2, 2.0 Hz, 1 H), 6.02 (dd, J=11.7, 2.0 Hz, 1 H),3.33 (s, 3 H)

[0051] Chlorosulfonic acid (2.0 ml) was added with1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene (1.00 g, 5.32 mmol) at0° C. and stirred for about 1 hour. The reaction solution was pouredinto ice water and extracted with ether, and the organic layer waswashed with saturated brine, dehydrated over MgSO₄ and thenconcentrated. A crude product of Compound V-2 was obtained (1.50 g,98%). Compound V-2: ¹H-NMR (400 MHz, CDCL₃) 7.93 (d, J=2.2 Hz, 1 H),7.74 (dd, J=8.6, 2.2 Hz, 1 H), 7.52 (d, J=8.6 Hz, 1 H), 1.73 (s, 4 H),1.33 (s, 6 H), 1.32 (s, 6 H)

[0052] Compound V-1 (200 mg, 0.93 mmol) and Compound V-2 (267 mg, 0.93mmol) were suspended in anhydrous pyridine (3 ml) and stirred at roomtemperature. After 2 hours, the reaction solution was added with waterand extracted with ethyl acetate, and the organic layer was washed with2 N hydrochloric acid and saturated brine, dehydrated over MgSO₄ andthen concentrated. The residue was purified by silica gel columnchromatography (ethyl acetate) to obtain Compound V-3 (50 mg, 12%).Compound V-3: ¹H-NMR (400 MHz, DMSO-d₆, 30° C.) 10.94 (b, 1 H), 7.73 (s,1 H), 7.58 (s, 2 H), 7.51 (d, J=10.7 Hz, 1 H), 7.30 (dd, J=13.5, 2.7 Hz,1 H), 7.21 (d, J=13.2 Hz, 1 H), 6.89 (dd, J=10.9, 2.7 Hz, 1 H), 3.42 (s,3 H), 1.63 (s, 4 H), 1.22 (s, 6 H), 1.20 (s, 6 H)

[0053] Compound V-3 (45 mg, 0.097 mmol) was dissolved in ethanol (3 ml)and 2 N sodium hydroxide (1 ml) and stirred at room temperature. After 6hours, the reaction solution was made acidic with 2 N hydrochloric acidand extracted with ethyl acetate, and the organic layer was washed withsaturated brine, dehydrated over MgSO₄ and then concentrated. A crudeproduct of Compound Tp40 was obtained (39 mg, quant). Compound Tp40:light yellow prisms (ethyl acetate/n-hexane); melting point 211° C.;¹H-NMR (400 MHz, DMSO-d₆, 30° C.) 10.11 (s, 1 H), 7.53 (d, J=2.2 Hz, 1H), 7.51 (d, J=8.3 Hz, 1 H), 7.44 (dd, J=8.3, 2.0 Hz, 1 H), 7.13 (d,J=12.2 Hz, 2 H), 7.19 (d, J=12.5 Hz, 2 H), 1.61 (s, 4 H), 1.21 (s, 6 H),1.13 (s, 6 H); Anal. Calcd. for C₂₁H₂₅N₁O₄S₁ C, (65.09%) H, (6.50%) N,(3.61%) Found C, (64.84%) H, (6.47%) N, (3.69)

Example 6 Synthesis of Compound Tp50

[0054]

[0055] Acid chloride VI-1 prepared from 3,5-di-t-butylbenzoic acid (550mg, 2.00 mmol) was added with Compound I-2 (158 mg, 1.15 mmol), pyridine(10 ml) and one piece of DMAP. After the starting materials disappeared,the reaction solution was poured into 2 N hydrochloric acid andextracted with methylene chloride, and the organic layer was dried oversodium sulfate. Then, the solvent was evaporated, and the residue waspurified by flash silica gel column chromatography (n-hexane:ethylacetate=2:1) to obtain Compound VI-2 (600 mg, 92%).

[0056] Compound V-2 (600 mg, 1.05 mmol) was dissolved in ethanol (10ml), added with 5% sodium hydroxide (10 ml) and stirred. After thestarting materials disappeared, the reaction solution was poured into 2N hydrochloric acid (30 ml), made pH 2 and extracted with ethyl acetate.The organic layer was dried over sodium sulfate, and the solvent wasevaporated. The residue was purified by ODS flash column chromatography(acetonitrile:water=2:1) to obtain Compound Tp50 (149 mg, 42%). CompoundTp50: light yellow prisms (methylene chloride/n-hexane); melting point236° C.; Anal. Calcd. for C₂₂H₂₇N₁O₃ C, (74.76%) H, (7.70%) N, (3.96%)Found C, (74.56%) H, (7.63%) N, (3.82%)

Example 7 Synthesis of Compound Tp60

[0057] 3,5-Bistrifluoromethylbenzoyl chloride (Compound VI-3, 560 mg,2.02 mmol), Compound I-2 (137 mg, 1.00 mmol), pyridine (5 ml) and onepiece of DMAP were added. After the starting materials disappeared, thereaction solution was poured into 2 N hydrochloric acid and extractedwith methylene chloride. The organic layer was dried over sodiumsulfate, and then the solvent was evaporated. The residue was purifiedby flash silica gel column chromatography (n-hexane:ethyl acetate=2:1)to obtain Compound VI-4 (500 mg, 80%). Compound VI-4: ¹H-NMR (400 MHz,CDCl₃) 9.00 (S, 1 H), 8.47 (s, 2 H), 8.39 (s, 2 H), 8.12 (s, 1 H), 8.03(s, 1 H), 7.70 (d, J=12.1 Hz, 2 H), 7.35 (d, J=12.1 Hz, 2 H)

[0058] Compound VI-4 (500 mg, 0.81 mmol) was dissolved in ethanol (6ml), added with 5% sodium hydroxide (3 ml) and stirred. After thestarting materials disappeared, the reaction solution was poured into 2N hydrochloric acid (30 ml), made pH 2 and extracted with methylenechloride. The organic layer was dried over sodium sulfate, and then thesolvent was evaporated. The residue was purified by ODS flash columnchromatography (acetonitrile:water=1:1) to obtain Compound Tp60 (160 mg,53%). Compound Tp60: light yellow prisms (methanol); melting point149-150° C.; ¹H-NMR (400 MHz, CDCl₃) 8.33 (s, 2 H), 8.09 (s, 1 H), 8.05(s, 1 H), 7.71 (d, J=11.3 Hz, 2 H), 7.38 (d, J=11.5 Hz, 2 H); Anal.Calcd. for C₁₆H₉N₁O₃F₆ C, (50.94%) H, (2.40%) N, (3.71%) Found C,(50.87%) H, (2.70%) N, (3.44%)

Example 8 Synthesis of Compounds Tp80, Tp82 and Tp84

[0059]

[0060] 5,6,7,8-Tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxylicacid (7.00 g, 30.2 mmol) was suspended in thionyl chloride (18.0 g) andanhydrous benzene (20 ml) and refluxed by heating. After 2 hours, thesolvent was evaporated, and the residue was added with 5-aminotropolone(2.07 g, 15.1 mmol), suspended in anhydrous pyridine (20 ml), added withone piece of DMAP and stirred at 100° C. After 1 hour, the reactionsolution was added with water and extracted with methylene chloride, andthe organic layer was washed with 2 N hydrochloric acid and saturatedbrine, dehydrated over MgSO₄ and then concentrated. The residue waspurified by silica gel column chromatography (ethyl acetate:methylenechloride=1:20) to obtain Compound VII-1 (6.96 g, 82%). Compound VII-1:¹H-NMR (400 MHz, CDCl₃) 8.13 (d, J=2.0 Hz, 1 H), 7.98 (s, 1 H), 7.90(dd, J=8.3, 2.0 Hz, 1 H), 7.86 (d, J=2.2 Hz, 1 H), 7.56 (dd, J=8.3, 2.0Hz, 1 H), 7.41 (d, J=8.3 Hz, 1 H), 7.40 (b, 1 H), 7.38 (d, J=8.3 Hz, 1H), 7.29 (bd, J=11.7 Hz, 2 H), 7.29 (b, 1 H), 1.72 (s, 8 H), 1.33 (s, 6H), 1.32 (s, 6 H), 1.31 (s, 6 H), 1.29 (s, 6 H)

[0061] Compound VII-1 (6.96 g, 12.3 mmol) was dissolved in methylenechloride (40 ml) and ethanol (40 ml), added with 2 N sodium hydroxide(30 ml) and stirred at room temperature. After 20 hours, the reactionsolution was made acidic with 2 N hydrochloric acid and extracted withethyl acetate. The organic layer was washed with saturated brine, driedover MgSO₄ and then concentrated. A mixture of a crude product ofTp80and 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoic acid (7.35 gin total, quant.) was obtained. This mixture (6.43 g) was dissolved inanhydrous pyridine (20 ml) and acetic anhydride (30 ml) and stirred atroom temperature. After 2 hours, the solvent was evaporated underreduced pressure, and the residue was purified by flash silica gelcolumn chromatography (ethyl acetate:methylene chloride=1:3) to obtainCompound VII-2 (4.12 g, 95%). Compound VII-2: ¹H-NMR (400 MHz, CDCl₃)7.87 (br s, 1 H), 7.84 (d, J=2.0 Hz, 1 H), 7.54 (dd, J=8.3, 2.0 Hz, 1H), 7.53 (b, 2 H), 7.43 (d, J=8.3 Hz, 1 H), 7.23 (d, J=12.0 Hz, 2 H),2.34 (s, 3 H), 1.72 (s, 4 H), 1.34 (s, 6 H), 1.31 (s, 6 H)

[0062] Compound VII-2 (4.12 g, 10.5 mmol) was dissolved in methylenechloride (50 ml) and ethanol (40 ml), added with 2 N sodium hydroxide(40 ml) and stirred at room temperature. After 2 hours, the reactionsolution was made acidic with 2 N hydrochloric acid and extracted withethyl acetate. The organic layer was washed with saturated brine,dehydrated over MgSO₄ and then concentrated to obtain a crude product ofTp80 (2.90 g, 91%). Tp80: light yellow scaly crystals (methanol);melting point 209° C.; ¹H-NMR (400 MHz, CDCl₃) 7.83 (d, J=2.0 Hz, 1 H),7.73 (s, 1 H), 7.71 (d, J=12.3 Hz, 2 H), 7.54 (dd, J=8.2 Hz, 1.8 Hz, 1H), 7.42 (d, J=8.3 Hz, 1 H), 7.36 (d, J=12.1 Hz, 2 H), 1.72 (8, 4 H),1.33 (s, 6 H), 1.31 (s, 6 H); Anal. Calcd. for C₂₂H₂₅NO₃ C, (75.19%) H,(7.17%) N, (3.99%) Found C, (75.24%) H, (7.27%) N, (3.90%)

[0063] NaH (60%, 31 mg, 0.76 mmol) was washed with n-hexane andsuspended in DMF (1 ml). The suspension was added with Compound VII-2(200 mg, 0.51 mmol) dissolved in DMF (3 ml) and stirred at roomtemperature. After 15 minutes, the reaction solution was added withmethyl iodide (0.1 ml) and stirred at room temperature. After 30minutes, the reaction solution was added with water and extracted withmethylene chloride. The organic layer was washed with saturated brine,dehydrated over MgSO₄ and then concentrated. The residue was purified byflash silica gel column chromatography (ethyl acetate:n-hexane=1:1) toobtain Compound VII-3 (136 mg, 66%). Compound VII-3: ¹H-NMR (400 M Hz,DMSO-d₆, 30° C.) 7.32 (d, J=8.1 Hz, 1 H), 7.26 (dd, J=8.1, 1.7 Hz, 1 H),7.16 (d, J=12.2 Hz, 2 H), 7.13 (d, J=1.7 Hz, 1 H), 7.10 (d, J=11.7 Hz, 2H), 3.35 (s, 3 H), 1.55 (s, 4 H), 1.18 (s, 6 H), 1.01 (s, 6 H)

[0064] Compound VII-3 (133 mg, 0.33 mmol) was dissolved in ethanol (8ml), added with 2 N sodium hydroxide (4 ml) and stirred at roomtemperature. After 2 hours, the reaction solution was made acidic with 2N hydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with saturated brine, dehydrated over MgSO₄ and thenconcentrated to obtain a crude product of Tp82 (120 mg, quant.). Tp82:light yellow scaly crystals (methylene chloride/n-hexane); melting point194° C.; ¹H-NMR (400 M Hz, DMSO-d₆, 30° C.) 7.28 (d, J=8.0 Hz, 1 H),7.27 (d, J=12.0 Hz, 1 H), 7.20 (dd, J=9.0, 1.7 Hz, 1 H), 7.07 (d, J=1.7Hz, 1 H), 7.01 (d, J=12.0 Hz, 2 H), 3.32 (s, 3 H), 1.53 (s, 4 H), 1.16(s, 6 H), 0.97 (s, 6 H); Anal. Calcd. for C₂₃H₂₇N₁O₃. 1/4H₂O C, (74.67%)H, (7.49%) N, (3.78%) Found C, (74.91%) H, (7.58%) N, (3.71%)

[0065] 5,6,7,8-Tetrahydro-3,5,5,8,8-pentamethylnaphthalene-2-carboxylicacid was used as a starting material to synthesize Compound Tp84 in thesame manner as that used for Compound Tp80. Tp84: light yellow powderycrystals (methylene chloride/n-hexane); melting point 206° C.; ¹H-NMR(400 MHz, CDCl₃) 7.72 (d, J=12.0 Hz, 2 H), 7.45 (bs, 1 H), 7.41 (s, 1H), 7.37 (d, J=12.0 Hz, 2 H), 7.20 (s, 1 H), 2.46 (s, 3 H), 1.70 (s, 4H), 1.30 (s, 6 H), 1.29 (s, 6 H); Anal. Calcd. for C₂₃H₂₇NO₃ C, (75.59%)H, (7.45%) N, (3.83%) Found C, (75.49%) H, (7.50%) N, (3.64%)

Example 9 Synthesis of Compound Tp88

[0066] 3-(1-Adamantyl)-4-methoxybenzoyl chloride was used as a startingmaterial to synthesize Compound Tp88 according to the method of Example6. Compound Tp88: light yellow powdery crystals (ethyl acetate); meltingpoint 142° C.; ¹H-NMR (400 MHz, DMSO-d₆, 30° C.) 10.16 (s, 1 H), 7.83(dd, J=8.6, 2.2 Hz, 1 H), 7.73 (d, J=2.4 Hz, 1 H), 7.72 (d, J=12.2 Hz, 1H), 7.22 (d, J=12.2 Hz, 2 H), 7.08 (d, J=8.8 Hz, 1 H), 3.88 (s, 3 H),2.07 (s, 6 H), 2.05 (s, 3 H), 1.74 (s, 6 H); Anal. Calcd. forC₂₅H₂₇N₁O₄.H₂O C, (70.90%) H, (6.90%) N, (3.31%) Found C, (71.19%) H,(6.94%) N, (3.31%)

Example 10 Synthesis of Compound Tp90

[0067](E)-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)acrylic acidchloride was used as the starting material to synthesize Compound Tp90according to the method of Example 6. Compound Tp90:yellow scalycrystals (ethanol/water); melting point 149° C.; ¹H-NMR (400 MHz,DMSO-d₆, 30° C.) 10.23 (s, 1 H), 7.82 (d, J=12.2 Hz, 2 H), 7.56 (d,J=15.6 Hz, 1 H), 7.56 (s, 1 H), 7.34-7.42 (m, 2 H), 7.25 (d, J=12.2 Hz,1 H), 6.75 (d, J=15.9 Hz, 1 H), 3.65 (s, 4 H), 1.27 (s, 6 H), 1.25 (s, 6H); Anal. Calcd. for C₂₄H₂₇N₁O₃.1/4H₂O C, (75.46%) H, (7.25%) N, (3.67%)Found C, (75.47%) H, (7.31%) N, (3.59%)

Example 11 Synthesis of Compound Tp93

[0068]

[0069](E)-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)acrylic acid(355 mg, 1.45 mmol) was suspended in thionyl chloride (1.73 g) andanhydrous benzene (5 ml) and refluxed. After 2 hours, the solvent wasevaporated, and the residue was added with Compound IV-1 (400 mg, 1.45mmol), suspended in anhydrous pyridine (5 ml), added with DMAP (53 mg,0.44 mmol) and stirred at 100° C. After 20 minutes, the reactionsolution was added with water and extracted with ethyl acetate, and theorganic layer was washed with 2 N hydrochloric acid and saturated brine,dehydrated over MgSO₄ and then concentrated. The residue was purified bysilica gel column chromatography (ethyl acetate:n-hexane=1:1) to obtainCompound Tp93 (48 mg, 9.2%). Compound Tp93: yellow prisms (ethylacetate); melting point 241° C.; ¹H-NMR (400 MHz, DMSO-d₆, 30° C.) 10.05(s, 1 H), 7.99 (d, J=11.0 Hz, 1 H), 7.91 (dd, J=11.0, 2.2 Hz, 1 H), 7.60(d, J=16.1 Hz, 1 H), 7.58 (d, J=2.2 Hz, 1 H), 7.55 (dd, J=13.2, 2.2 Hz,1 H), 7.36-7.42 (m, 2 H), 7.24 (d, J=13.2 Hz, 1 H), 6.78 (d, J=15.7 Hz,1 H), 1.65 (s, 4 H), 1.27 (s, 6 H), 1.24 (s, 6 H)

Example 12 Synthesis of Compound Tp95

[0070](E,E)-5-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)-2,4-pentadienoicacid chloride was used as the starting material to synthesize CompoundTp95 according to the method of Example 6. Compound Tp95: light yellowprisms (methanol); melting point 216° C.; ¹H-NMR (400 MHz, CDCl₃) 7.71(d, J=11.9 Hz, 2 H), 7.53 (dd, J=10.8 Hz, 14.9 Hz, 1 H), 7.29-7.37 (m, 5H), 7.18 (brs, 1 H), 6.95 (d, J=15.2 Hz, 1 H), 6.85 (dd, J=10.8 Hz, 15.4Hz, 1 H), 6.04 (d, J=14.7 Hz, 1 H), 1.70 (s, 4 H), 1.31 (s, 6 H), 1.29(s, 6 H)

Example 13 Synthesis of Compounds Tp140, Tp141 and Tp145

[0071]

[0072] 2-Bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (3.00g, 11.2 mmol) and copper iodide (237 mg, 1.12 mmol) were dissolved intriethylamine (25 ml) under an argon atmosphere. The reaction solutionwas added with TMS acetylene (3.31 g, 33.7 mmol) and Pd(PPh₃)₂Cl₂ (786mg, 1.12 mmol) and stirred at 70° C. After 22 hours, the reactionsolution was returned to room temperature, extracted with ether andfiltered, and the ether layer was washed with water and NH₄OH/NH₄Cl=9/1aqueous solution, water, 1 N hydrochloric acid and saturated brine,dehydrated over MgSO₄ and then concentrated. The residue was purified bysilica gel column chromatography (n-hexane) to obtain Compound VIII-1(2.51 g, 79%). Compound VIII-1: ¹H-NMR (400 MHz, CDCL₃) 7.40 (s, 1 H),7.21 (s, 2 H), 1.66 (s, 4 H), 1.26 (s, 6 H), 1.25 (s, 6 H), 0.24 (s, 9H)

[0073] Compound VIII-1 (1.00 g, 3.52 mmol) was dissolved in methanol (15ml), added with potassium carbonate (97 mg, 0.70 mmol) and stirred atroom temperature for 24 hours. The reaction solution was added withwater and extracted with ethyl acetate, and the organic layer was washedwith saturated brine, dehydrated over MgSO₄ and then concentrated. Theresidue was purified by silica gel column chromatography (ethylacetate:n-hexane=1:50) to obtain Compound VIII-2 (700 mg, 94%). CompoundVIII-2: 1H-NMR (400 MHz, CDCL₃) 7.44 (s, 1 H), 7.26 (s, 2 H), 3.01 (s, 4H), 1.27 (s, 6 H), 1.26 (s, 6 H)

[0074] Compound VIII-2 (136 mg, 0.64 mmol) and Compound II-2 (160 mg,0.61 mmol) were suspended in triethylamine (6.0 ml) and bubbled withargon to attain sufficient substitution. This suspension was added withPd(PPh₃)₂Cl₂ (112 mg, 0.16 mmol) and copper iodide (30.5 mg, 0.16 mmol),further bubbled with argon and stirred at room temperature for 24 hours.The reaction solution was filtered through Cerite and extracted withether, and the organic layer was washed with saturated brine, dehydratedover MgSO₄ and then concentrated. The residue was purified by flashsilica gel column chromatography (ethyl acetate:n-hexane=2:1) to obtainCompound Tp141 (171 mg, 81%). Compound Tp141: yellow needle crystals(methylene chloride/n-hexane); melting point 139° C.; ¹H-NMR (400 MHz,DMSO-d₆, 30° C.) 7.50 (d, J=1.7 Hz, 1 H), 7.41-7.46 (m, 2 H), 7.37 (d,J=8.1 Hz, 1 H), 7.28 (dd, J=8.1, 2.0 Hz, 1 H), 7.02 (d, J=13.0 Hz, 1 H),6.97 (d, J=11.0 Hz, 1 H), 3.89 (s, 3 H), 1.65 (s, 4 H), 1.26 (s, 6 H),1.25 (s, 6 H); Anal. Calcd. for C₂₄H₂₆O₂ C, (83.20%) H, (7.56%) Found C,(82.93%) H, (7.63%)

[0075] Compound Tp141 (125 mg, 0.36 mmol) was dissolved in ethanol (8ml) and 2 N sodium hydroxide (4 ml) and stirred at room temperature.After 3 hours, the reaction solution was made acidic with 2 Nhydrochloric acid and extracted with ethyl acetate, and the organiclayer was washed with saturated brine and dehydrated over MgSO₄ and thenconcentrated to obtain a crude product of Compound Tp140 (123 mg,quant). Compound Tp140: yellow needle crystals (ethyl acetate); meltingpoint 182° C.; ¹H-NMR (400 MHz, DMSO-d₆, 30° C.) 7.53 (d, J=11.7 Hz, 2H), 7.48 (d, J=1.7 Hz, 1 H), 7.36 (d, J=8.1 Hz, 1 H), 7.26 (dd, J=8.1,1.8 Hz, 1 H), 7.09 (d, J=11.7 Hz, 2 H), 1.64 (s, 4 H), 1,25 (s, 6 H),1.24 (s, 6 H); Anal. Calcd. for C₂₃H₂₄O₂ C, (83.10%) H, (7.28%) Found C,(82.83%) H, (7.42%)

[0076] 2-Bromo-5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalene wasused as a starting material to synthesize Compound Tp145 in the samemanner as that used for Compound Tp140. Compound Tp145: yellow prismaticcrystals (methylene chloride/n-hexane), melting point 137° C.; ¹H-NMR(400 M Hz, CDCl₃) 7.62 (d, J=12.0 Hz, 2 H), 7.42 (s, 1 H), 7.30 (d,J=12.0 Hz, 2 H), 7.16 (s, 1 H), 2.43 (s, 3 H), 1.68 (s, 4 H), 1.284 (s,6 H), 1.278 (s, 6 H); Anal. Calcd. for C₂₄H₂₆O₂ C, (83.20%) H, (7.56%)Found C, (82.92%) H, (7.73%)

Example 14 Synthesis of Compounds Tp146 and Tp149

[0077] Compound Tp141 (332 mg, 0.96 mmol), methanol (2 ml), water (2 ml)and 80% hydrazine hydrate (2 ml) were heated on a boiling water bath forabout 10 minutes. The reaction solution was left stand for cooling toroom temperature and then cooled with ice, and the precipitates werecollected by filtration, sufficiently washed with water and dried underreduced pressure to obtain a crude product of Compound Tp146 (299 mg,90%). Compound Tp146: ¹H-NMR (400 MHz, DMSO-d₆, 30° C.) 9.19 (s, 1 H),7.48 (dd, J=11.5, 1.7 Hz, 1 H), 7.41 (d, J=1.7 Hz, 1 H), 7.36 (dd,J=12.2, 1.7 Hz, 1 H), 7.32 (d, J=8.3 Hz, 1 H), 7.21 (dd, J=8.0, 1.7 Hz,1 H), 6.99 (d, J=11.2 Hz, 1 H), 6.74 (d, J=12.0 Hz, 1 H), 5.00 (bs, 2H), 1.64 (s, 4 H), 1.25 (s, 6 H), 1.23 (s, 6 H)

[0078] Compound Tp146 (250 mg, 0.72 mmol) was suspended in acetic acid(1 ml) and water (4 ml) and refluxed by heating. The suspension wasadded with a hot 10% copper sulfate solution (8 ml) and stirred. Thirtyminutes after ceasing of the gas generation, the reaction solution wascooled to room temperature and extracted with ethyl acetate, and theorganic layer was washed with 2 N hydrochloric acid and saturated brine,dried over MgSO₄ and then concentrated. The residue was purified byflash silica gel column chromatography (methylene chloride:ethylacetate=100:1) to obtain Compound Tp149 (15 mg, 6.6%). Compound Tp149:¹H-NMR (400 MHz, CDCL₃) 7.45 (d, J=1.7 Hz, 1 H), 7.30 (d, J=10.7 Hz, 1H), 7.28 (d, J=10.3 Hz, 1 H), 7.22-7.26 (m, 2 H), 7.08 (dd, J=12.0, 8.5Hz, 1 H), 6.97-7.003 (m, 2 H), 1.57 (s, 4 H), 1.30 (s, 6 H), 1.28 (s, 6H)

Example 15 Synthesis of Compound Tp150

[0079] Compound Tp141 (80 mg, 0.23 mmol) was dissolved in ethanol (5 ml)and added with Pd/C (20 mg) to perform catalytic hydrogen reduction atroom temperature. After 2 hours, the reaction solution was filtered toremove the insoluble matter, and the solvent was concentrated. Theresidue was purified by flash silica gel column chromatography (ethylacetate:n-hexane=2:1) to obtain Compound VIII-3 (35 mg, 43%). CompoundVIII-3: ¹H-NMR (400 MHz, CDCL₃) 7.23 (d, J=8.3 Hz, 1 H), 7.22 (d, J=11.0Hz, 1 H), 7.14 (dd, J=12.4, 2.0 Hz, 1 H), 7.00 (d, J=2.0 Hz, 1 H), 6.94(dd, J=8.1, 2.0 Hz, 1 H), 6.85 (d, J=10.2 Hz, 1 H), 6.64 (d, J=10.5 Hz,1 H), 3.92 (s, 3 H), 2.83 (s, 4 H), 1.66 (s, 4 H), 1.27 (s, 6 H), 1.22(s, 6 H)

[0080] Compound VIII-3 (34 mg, 0.097 mmol) was dissolved in ethanol (2ml), added with 2 N sodium hydroxide (1 ml) and stirred at roomtemperature. After 12 hours, the reaction solution was warmed to 70° C.and further stirred for 6 hours. The reaction solution was made acidicwith 2 N hydrochloric acid and extracted with ethyl acetate, and theorganic layer were washed with saturated brine, dried over MgSO₄ andthen concentrated to obtain a crude product of Compound Tp150 (28 mg,86%). Compound Tp150: light yellow scaly crystals (ethanol/water),melting point 138° C.; ¹H-NMR (400 MHz, DMSO-d₆, 30° C.) 7.29 (d, J=11.5Hz, 2 H), 7.19 (d, J=8.3 Hz, 1 H), 7.12 (d, J=11.7 Hz, 2 H), 7.05 (d,J=2.0 Hz, 1 H), 6.96 (dd, J=8.3, 2.0 Hz, 1 H), 2.70-2.85 (m, 4 H), 1.60(s, 4 H), 1.20 (s, 6 H), 1.17 (s, 6 H); Anal. Calcd. for C₂₃H₂₈O₂.1/4H2OC, (81.02%) H, (8.42%) Found C, (80.85%) H, (8.28%)

Example 16 Synthesis of Compound Tp155

[0081] 1-Bromo-3,5-di-(tert-butyl)benzene was used as a startingmaterial to synthesize Compound Tp155 according to the method of Example15. Compound Tp155: yellow needle crystals (ethanol); melting point 204°C.; ¹H-NMR (400 MHz, DMSO-d₆, 30° C.) 7.60 (d, J=11.7 Hz, 2 H), 7.45 (t,J=1.7 Hz, 1 H), 7.36 (d, J=1.7 Hz, 2 H), 7.16 (d, J=12.0 Hz, 2 H), 1.29(s, 18 H); Anal. Calcd. for C₂₃H₂₆O₂ C, (82.60%) H, (7.84%) Found C,(82.46%) H, (7.93%)

Example 17 Synthesis of Compound Tp160

[0082]

[0083] 2-Amino-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (102mg, 0.50 mmol) was added with 30% sulfuric acid (2 ml) and heated withstirring. Soon after the compound was dissolved, the solution was cooledwith ice. The reaction solution was added with sodium nitrate (70 mg)and water (2 ml) and stirred. Then, the solution was added with asolution of tropolone (70 mg, 0.57 mmol) dissolved in 10% sodiumhydroxide (2 ml) and stirred. After the reaction was completed, thereaction solution was poured into water and extracted with methylenechloride. The organic layer was dried over sodium sulfate, and then thesolvent was evaporated. The residue was purified by ODS flash columnchromatography (methanol) to obtain Compound Tp160 (38 mg, 23%).Compound Tp160: red needle crystals (methanol/methylene chloride);melting point 185° C.; ¹H-NMR (400 MHz, CD₃OD) 8.21 (dd, J=1.6 Hz, 10.7Hz, 2 H), 7.90 (d, J=2.0 Hz, 1 H), 7.65 (dd, J=2.0 Hz, 8.4 Hz, 1 H),7.49 (dd, J=1.3 Hz, 10.5 Hz, 2 H), 7.45 (d, J=8.4 Hz, 1 H), 1.74 (s, 4H), 1.37 (s, 6 H), 1.33 (s, 6 H)

Example 18 Synthesis of Compound Tp170

[0084] 3,5-Di(tert-butyl)aniline was used as a starting material tosynthesize Compound Tp170 according to the method of Example 17.Compound Tp170: orange needle crystals (ethanol); melting point 199-201°C.; ¹H-NMR (400 MHz, DMSO-d₆, 30° C.) 8.12 (d, J=12.0 Hz, 2 H), 7.71 (d,J=1.7 Hz, 2 H), 7.61 (d, J=1.7 Hz, 1 H), 7.36 (d, J=11.7 Hz, 2 H), 1.35(s, 18 H); Anal. Calcd. for C₂₁H₂₆N₂O₂ C, (74.53%) H, (7.74%) N, (8.28%)Found C, (74.38%) H, (7.80%) N, (8.19%)

Example 19 Synthesis of Compound Tp175

[0085] 3,5-Di(tert-butyl)aniline and 4-isopropyltropolene were used asstarting materials to synthesized Compound Tp175 Compounded according tothe method of Example 17. Compound Tp175: red needle crystals(ethanol/water); melting point 145° C.; ¹H-NMR (400 MHz, DMSO-d₆, 30°C.) 7.91 (d, J=12.7 Hz, 1 H), 7.88 (s, 1 H), 7.50-7.55 (m, 2 H), 7.35(s, 1 H), 7.19 (d, J=12.7 Hz, 1 H), 4.32 (h, J=6.8 Hz, 1 H), 1.69 (s, 4H), 1.32 (s, 6 H), 1.29 (s, 3 H), 1.28 (s, 6 H), 1.28 (s, 3 H); Anal.Calcd. for C₂₄H₃₀N₂O₂ C, (76.16%) H, (7.99%) N, (7.40%) Found C,(75.88%) H, (7.96%) N, (7.44%)

Example 20 Synthesis of Compound Tp180

[0086]

[0087] 2,5-Dichloro-2,5-dimethylhexane (1.73 g, 9.48 mmol) and4-bromobiphenyl (2.00 g, 8.58 mmol) were dissolved in methylene chloride(10 ml) and gradually added with aluminum chloride (63 mg) with stirringunder ice cooling. After the reaction solution was stirred for 7 hoursat room temperature, the mixture was poured into ice water and extractedwith methylene chloride, and the organic layer was washed with water, 2N hydrochloric acid and saturated brine, dehydrated over MgSO₄ and thenconcentrated. Acrude product of Compound X-1 was obtained (2.90 g, 99%).Compound X-1: ¹H-NMR (400 MHz, CDCL₃) 7.53 (d, J=8.6 Hz, 2 H), 7.47 (d,J=2.0 Hz, 1 H), 7.43 (d, J=8.6 Hz, 2 H), 7.37 (d, J=8.3 Hz, 1 H), 7.31(dd, J=8.3, 2.2 Hz, 1 H), 1.72 (s, 4 H), 1.33 (s, 6 H), 1.31 (s, 6 H);Anal. Calcd. for C₂₁H₂₄N₂O₂.1/4H₂O C, (73.98%) H, (7.24%) N, (8.22%)Found C, (74.11%) H, (7.27%) N, (8.28%)

[0088] Compound X-1 (275 mg, 0.80 mmol) was dissolved in THF (3 ml),added with a 1.6 M solution of n-BuLi (0.96 mmol) in hexane (0.60 ml) at−78° C. and stirred for 30 minutes. This solution was added to asolution of zinc chloride (109 mg, 0.80 mmol) dissolved in THF (2 ml)and stirred at room temperature. After 1 hour, the reaction solution wasadded to a solution of Compound I-4 (152 mg, 0.54 mmol) and Pd(PPh₃)₄(46 mg, 0.040 mmol) dissolved in THF (4 ml) and stirred at roomtemperature. After 4.5 hours, the reaction solution was added with waterand extracted with ethyl acetate, and the organic layer was washed with2 N hydrochloric acid and saturated brine, dehydrated over MgSO₄ andthen concentrated. The residue was purified by flash silica gel columnchromatography (ethyl acetate:n-hexane=2:1 and methylene chloride:ethylacetate=3:2) to obtain Compound X-2 (91 mg, 29%). Compound X-2: ¹H-NMR(400 MHz, CDCl₃) 7.66 (d, J=8.3 Hz, 2 H), 7.60 (dd, J=12.7, 2.0 Hz, 1H), 7.52-7.56 (m, 3 H), 7.33-7.41 (m, 3 H), 7.36 (dd, J=12.4, 2.0 Hz, 1H), 6.88 (d, J=10.5 Hz, 1 H), 4.01 (s, 3 H), 1.74 (s, 4 H), 1.36 (s, 6H), 1.33 (s, 6 H)

[0089] Compound X-2 (85 mg, 0.21 mmol) was dissolved in ethanol (8 ml),added with 2 N sodium hydroxide (3 ml) and stirred at room temperature.After 6 hours, the reaction solution was made acidic with 2 Nhydrochloric acid and extracted with ethyl acetate, and the organiclayer was washed with saturated brine, dehydrated over MgSO₄ and thenconcentrated. The residue was recrystallized from ethyl acetate/n-hexaneto obtain Compound Tp180 (20 mg, 24%). Compound Tp180: yellow greenneedle crystals (ethyl acetate/n-hexane); melting point 212° C.; ¹H-NMR(400 MHz, DMSO-d₆, 30° C.) 7.73 (d, J=8.3 Hz, 2 H), 7.71 (d, J=10.8 Hz,2 H), 7.65 (d, J=8.3 Hz, 2 H), 7.59 (d, J=1.6 Hz, 1 H), 7.45 (dd, J=8.3,1.6 Hz, 1 H), 7.40 (dd, J=8.0 Hz, 1 H), 1.67 (s, 4 H), 1.31 (s, 6 H),1.27 (s, 6 H)

Example 21 Synthesis of Compound Tp190

[0090] 3-Bromobiphenyl was used as a starting material to synthesizeCompound Tp190 according to the method of Example 20. Compound Tp190:white powder (ethyl acetate/n-hexane), melting point 140° C.; ¹H-NMR(400 MHz, DMSO-d₆, 30° C.) 7.75 (d, J=12.0 Hz, 2 H), 7.75 (bs, 1 H),7.63 (dt, J=4.4, 7.3 Hz, ,1 H), 7.60 (d, J=2.0 Hz, 1 H), 7.53 (d, J=4.9Hz, 2 H), 7.45 (dd, J=8.3, 2.0 Hz, 1 H), 7.40 (d, J=8.3 Hz, 1 H), 7.30(d, J=11.8 Hz, 2 H), 1.67 (s, 4 H), 1.31 (s, 6 H), 1.27 (s, 6 H)

Example 22 Synthesis of Compound Tp200

[0091]

[0092] 2-Bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene (3.00g, 11.2 mmol) and Pd(PPh₃)₄ (416 mg, 0.36 mmol) were dissolved indimethoxyethane (3.6 ml) under an argon atmosphere and stirred for 10minutes. The reaction solution was added with 2-furanboronic acid (1.45g, 12.9 mmol), immediately added with 1 M aqueous sodium carbonate (28ml) and refluxed. After 5.5 hours, the reaction solution was cooled toroom temperature. The solvent was evaporated, and the residue was addedwith water and extracted with ether. The insoluble solids were removedby filtration, and the filtrate was washed with saturated brine,dehydrated over MgSO₄ and then concentrated. The residue was purified bysilica gel column chromatography (ethyl acetate:n-hexane=1:50) to obtainCompound XI-1 (1.00 g, 35%). Compound XI-1: ¹H-NMR (400 MHz, CDCL₃) 7.61(d, J=2.0 Hz, 1 H), 7.44 (d, J=1.1 Hz, 1 H), 7.42 (dd, J=8.1, 2.0 Hz, 1H), 7.31 (d, J=8.3 Hz, 1 H), 6.58 (d, J=3.4 Hz, 1 H), 6.44 (dd, J=3.1,1.1 Hz, 1 H), 1.70 (s, 4 H), 1.33 (s, 6 H), 1.29 (s, 6 H)

[0093] Compound XI-1 (497 mg, 1.96 mmol) was dissolved in THF (4 ml),added with a 1.6 M solution of n-BuLi (2.94 mmol) in hexane (1.84 ml) at−78° C. and stirred for 30 minutes. This solution was added to asolution of zinc chloride (267 mg, 1.96 mmol) dissolved in THF (4 ml)and stirred at room temperature. After 1 hour, the reaction solution wasadded to a solution of Compound I-4 (370 mg, 1.30 mmol) and Pd(PPh₃)₄(75 mg, 0.065 mmol) dissolved in THF (6 ml) and stirred at roomtemperature. After 1.5 hours, the reaction solution was added with waterand extracted with ethyl acetate, and the organic layer was washed with2 N hydrochloric acid and saturated brine, dehydrated over MgSO₄ andthen concentrated. The residue was purified by flash silica gel columnchromatography (ethyl acetate) to obtain Compound XI-2 (142 mg, 19%).Compound XI-2: ¹H-NMR (400 MHz, DMSO-d₆, 30° C.) 7.81 (dd. J=12.7, 2.0Hz, 1 H), 7.71 (d, J=1.7 Hz, 1 H), 7.69 (dd, J=10.3, 1.7 Hz, 1 H), 7.54(dd, J=8.3 1.9 Hz, 1 H), 7.39 (d, J=8.3 Hz, 1 H), 7.15 (d, J=3.7 Hz,1H), 7.12 (d, J=10.5 Hz, 1 H), 7.09 (d, J=12.9 Hz, 1 H), 7.07 (d, J=3.7Hz, 1 H), 3.89 (s, 3 H), 1.66 (s, 4 H), 1.31 (s, 6 H), 1.26 (s, 6 H)

[0094] Compound XI-2 (135 mg, 0.35 mmol) was dissolved in ethanol (4ml), added with 2 N sodium hydroxide (1.5 ml) and stirred at roomtemperature. After 2 hours, ethanol was evaporated, and the residue wasadded with 2 N sodium hydroxide. The precipitates were collected byfiltration and sufficiently washed with ethyl acetate. The crudecrystals were suspended in water, and the suspension was made acidicwith 2 N hydrochloric acid and extracted with ethyl acetate. The organiclayer was washed with saturated brine, dehydrated over MgSO₄ and thenconcentrated. A crude product of Compound Tp200 was obtained (19 mg,15%). Compound Tp200: orange powder (ethanol/water); melting point 173°C.; ¹H-NMR (400 MHz, DMSO-d₆, 30° C.) 7.91 (d, J=12.0 Hz, 2 H), 7.70 (d,J=1.7 Hz, 1 H), 7.55 (dd, J=8.0, 2.0 Hz, 1 H), 7.38 (d, J=8.3 Hz, 1 H),7.28 (d, J=12.0 Hz, 2 H), 7.16 (d, J=3.7 Hz, 1 H), 7.08 (d, J=3.7 Hz, 1H), 1.66 (s, 4 H), 1.32 (s, 6 H), 1.26 (s, 6 H); Anal. Calcd. forC₂₅H₂₆O₃.1/4H₂O C, (79.23%) H, (7.05%) Found C, (79.43%) H, (7.12%)

Example 23 Synthesis of Compound Tp210

[0095] 2-Thiopheneboronic acid was used as a starting material tosynthesize Compound Tp210 according to the method of Example 22.Compound Tp210: yellow needle crystals (ethyl acetate/n-hexane); meltingpoint 176° C.; ¹H-NMR (400 MHz, DMSO-d₆, 30° C) 7.80 (d, J=12.2 Hz, 2H), 7.57 (d, J=3.9 Hz, 1 H), 7.51 (d, J=3.9 Hz, 1 H), 7.42 (dd, J=8.3,2.2 Hz, 1 H), 7.37 (d, J=8.6 Hz, 1 H), 7.24 (d, J=12.0 Hz, 1 H), 1.66(s, 4 H), 1.29 (s, 6 H), 1.25 (s, 6 H); Anal. Calcd. for C₂₅H₂₆O₂S₁C,(76.89%) H, (6.71%) Found C, (76.68%) H, (6.84%)

Example 24 Synthesis of Compound Tp250

[0096]

[0097] 2-Bromonaphthalene (3.00 g, 14.5 mmol) and2,5-dichloro-2,5-dimethylhexane (2.92 g, 15.9 mmol) were suspended inanhydrous methylene chloride (24 ml) and added with aluminum chlorideunder ice cooling (300 mg). After the reaction solution was stirred for6 hours, the mixture was poured into ice water at room temperature andextracted with ethyl acetate, and the organic layer was washed withwater, saturated aqueous sodium hydrogencarbonate and saturated brine,dehydrated over MgSO₄ and then concentrated. The crude crystals weresuspended in ether, and the insoluble solids were removed by filtration.The filtrate was concentrated and purified by silica gel columnchromatography (n-hexane) to obtain Compound XII-1 (2.88 g, 63%).Compound XII-1: ¹H-NMR (400 MHz, CDCL₃) 7.90 (d, J=2.0 Hz, 1 H), 7.73(s, 1 H), 7.67 (s, 1 H), 7.59 (d, J=8.6 Hz, 1 H), 7.41 (dd, J=9.4, 2.0Hz, 1 H), 1.76 (s, 4 H), 1.38 (s, 6 H), 1.38 (s, 6 H)

[0098] Compound XII-1 (796 mg, 2.51 mmol) was dissolved in THF (5 ml),added with n-butyl lithium (1.6 M solution in hexane) (2.35 ml, 3.77mmol) at −78° C. and stirred for 30 minutes. This solution was added toa solution of zinc(II) chloride (342 mg, 2.51 mmol) dissolved in THF (4ml) and stirred at room temperature for 1 hour. Further, this solutionwas added to a solution of Compound I-4 (415 mg, 1.67 mmol) andPd(PPh₃)₄ (96 mg, 0.08 mmol) dissolved in THF (7 ml) and stirred at roomtemperature. After 2 hours, the reaction solution was added with waterand extracted with ethyl acetate, and the organic layer was washed with2 N hydrochloric acid and saturated brine, dehydrated over MgSO₄ andthen concentrated. The residue was purified by flash silica gel columnchromatography (ethyl acetate) to obtain Compound XII-2 (198 mg, 21%).Compound XII-2: ¹H-NMR (400 MHz, DMSOd₆, 30° C.) 8.02 (s, 1 H), 7.94 (s,1 H), 7.90 (s, 1 H), 7.89 (d, J=9.3 Hz, 1 H), 7.75 (dd, J=12.9, 2.2 Hz,1 H), 7.49-7.63 (m, 2 H), 7.17 (d, J=12.7 Hz, 1 H), 7.11 (d, J=10.7 Hz,1 H), 3.90 (s, 3 H), 1.74 (s, 4 H), 1.37 (s, 12 H)

[0099] Compound XII-2 (150 mg, 0.40 mmol) was dissolved in ethanol (7ml), added with 2 N sodium hydroxide (3 ml) and stirred at 70° C. After30 minutes, ethanol was evaporated, and the residue was added with 2 Nsodium hydroxide to sufficiently deposit crystals. The crystals werecollected by filtration, and this salt was suspended in water, madeacidic with 2 N hydrochloric acid and extracted with ethyl acetate. Theorganic layer was washed with saturated brine, dehydrated over MgSO₄ andthen concentrated. A crude product of Compound Tp250 was obtained (89mg, 62%). Compound Tp250: light yellow scaly crystals (ethylacetate/n-hexane); melting point 192° C.; ¹H-NMR (400 MHz, DMSO-d₆, 30°C.) 8.03 (s, 1 H), 7.95 (s, 1 H), 7.90 (s, 1 H), 7.89 (d, J=9.5 Hz, 1H), 7.78 (d, J=11.9 Hz, 2 H), 7.60 (dd, J=8.3, 1.7 Hz, 1 H), 7.33 (d,J=11.7 Hz, 2 H), 1.74 (s, 4 H), 1.37 (s, 12 H); Anal. Calcd. forC₂₅H₂₆O₂ C, (83.76%) H, (7.31%) Found C, (83.49%) H, (7.52%)

Example 25 Synthesis of Compound Tp260

[0100]

[0101] 5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenethiol (550mg, 2.50 mmol) was dissolved in DMF (4 ml), added with potassiumcarbonate (691 mg, 5.00 mmol) and bromoacetaldehyde/diethylacetal (0.45ml, 591 mmol, 3.00 mmol) at room temperature and stirred at 140° C.After 3 hours, the reaction solution was cooled to room temperature,added with water and extracted with ethyl acetate, and the organic layerwas washed with saturated brine, dried over MgSO₄ and then concentrated.The residue was purified by flash silica gel column chromatography(ethyl acetate:n-hexane=1:16) to obtain Compound XIII-1 (677 mg, 81%).Compound XIII-1: ¹H-NMR (400 MHz, CDCL₃) 7.32 (d, J=2.0 Hz, 1 H), 7.21(d, J=8.3 Hz, 1 H), 7.15 (dd, J=8.3, 2.2 Hz, 1 H), 4.64 (t, J=5.6 Hz, 1H), 3.66 (q, J=7.1 Hz, 2 H), 3.54 (q, J=7.1 Hz, 2 H), 3.10 (d, J=5.6 Hz,2 H), 1.66 (s, 4 H), 1.26 (s, 6 H), 1.25 (s, 6 H), 1.19 (t, J=7.1 Hz, 6H)

[0102] Compound XIII-2 (673 mg, 2.00 mmol) was dissolved in toluene (2.5ml), added to PPA (2.0 g) and stirred at 90° C. After 1 hour, thereaction solution was cooled to room temperature, added with water andextracted with ethyl acetate, and the organic layer was washed withsaturated brine, dried over MgSO₄ and then concentrated. The residue waspurified by flash silica gel column chromatography (methylenechloride:n-hexane=1:10) to obtain Compound XIII-2 (309 mg, 63%).Compound XIII-2: ¹H-NMR (400 MHz, CDCL₃) 7.82 (s, 1 H), 7.77 (s, 1 H),7.31 (d, J=5.4 Hz, 1 H), 7.22 (d, J=4.9 Hz, 1 H), 1.75 (s, 4 H), 1.36(s, 6 H), 1.35 (s, 6 H)

[0103] Compound XIII-2 (192 mg, 0.79 mmol) was dissolved in THF (2 ml),added with a 1.6 M solution of n-BuLi (1.19 mmol) in hexane (0.74 ml) at−78° C. and stirred for 30 minutes. This solution was added to asolution zinc chloride (108 mg, 0.79 mmol) dissolved in THF (2 ml) andstirred at room temperature. After 1 hour, the reaction solution wasadded to a solution of Compound II-2 (149 mg, 0.52 mmol) and Pd(PPh₃)₄(30 mg, 0.026 mmol) dissolved in THF (4 ml) and stirred at roomtemperature. After 3 hours, the reaction solution was added with waterand extracted with ethyl acetate, and the organic layer was washed with2 N hydrochloric acid and saturated brine, dehydrated over MgSO₄ andthen concentrated. The residue was purified by flash silica gel columnchromatography (methylene chloride:ethyl acetate=2:1 and ethylacetate:n-hexane=2:1) to obtain Compound XIII-3 (34 mg, 15%). CompoundXIII-3: ¹H-NMR (400 MHz, CDCL₃) 7.75 (s, 1 H), 7.72 (s, 1 H), 7.71 (dd,J=12.7, 2.0 Hz, 1 H), 7.43 (s, 1 H), 7.43 (dd, J=10.5, 2.0 Hz, 1 H),7.30 (d, J=12.7 Hz, 1 H), 6.82 (d, J=10.7 Hz, 1 H), 3.99 (s, 3 H), 1.75(s, 4 H), 1.36 (s, 12 H)

[0104] Compound XIII-3 (32 mg, 0.085 mmol) was dissolved in ethanol (2ml), added with 2 N sodium hydroxide (1 ml) and stirred at roomtemperature. After 3 hours, the reaction solution was made acidic with 2N hydrochloric acid and extracted with ethyl acetate, and the organiclayer was washed with saturated brine, dried over MgSO₄ and thenconcentrated. A crude product of Compound Tp260 was obtained (32 mg,quant). Compound Tp260: brown prismatic crystals (ethylacetate/n-hexane), melting point 172° C.; ¹H-NMR (400 MHz, DMSO-d₆, 30°C.) 7.91 (s, 1 H), 7.81 (d, J=12.0 Hz, 2 H), 7.78 (s, 1 H), 7.74 (s, 1H), 7.27 (d, J=12.0 Hz, 2 H), 1.69 (s, 4 H), 1.32 (s, 12 H); Anal.Calcd. for C₂₃H₂₄O₂S₁ C, (75.79%) H, (6.64%) Found C, (75.49%) H,(6.69%)

Test Example 1 Test for Induction of Cell Differentiation in HL-60 Cells

[0105] For each of the compounds of the examples, action for inducingcell differentiation was examined for each alone and in combination with1×10⁻⁷ M of HX630. According to the methods described in Japanese PatentUnexamined Publication (KOKAI) No. (Sho)61-76440/1986, differentiationof the cells of promyelocyte leukemia cell strain HL-60 intogranulocytic series cells was determined based on morphological changeand measurement of ability to reduce nitro blue tetrazolium (NBT). Theratios (%) of differentiated cells shown in the following table arethose calculated from NBT reduction ability. HX630 is a retinoidsynergist that enhances actions of retinoids, and the concentrations of−8, −7 and −6 mean that each compound was added at concentrations of1×10⁻⁸ M, 1×10⁻⁷ M and 1×10⁻⁶ M, respectively. TABLE 2 Ratio of cellsfor which Ratio of cells differentiation was induced by for whichdifferentiation each compound in was induced by each combination withcompound alone (%) 1 × 10⁻⁷ M of HX630 (%) Concentration ConcentrationCompound −8 −7 −6 −8 −7 −6 Tp05 0.6 0.5 13 1.2 1.2 35 Tp10 6.8 2.9 3.3 32.9 5.6 Tp20 2.1 1.8 2.7 4.6 3.7 2.4 Tp22 2.8 2.4 18 2.1 3.3 78 Tp30 1.31.5 1.2 2.5 2.3 20 Tp40 1.3 0.9 2.3 1.8 2.5 2 Tp50 1.6 2.8 5.1 Tp60 0.81.3 2.1 2.2 21.2 37.8 Tp80 7 26 21 82 85 79 Tp82 0.5 1.2 1.4 1.9 7 42Tp84 0.7 5 26 15 89 90 Tp88 0.9 1.2 46 2.6 14 62 Tp90 0.7 0.9 67 1.5 2.143 Tp93 0.6 0.8 9 3.6 0.8 40 Tp95 0.5 0.5 0.3 0.8 0.5 1.7 Tp140 65 73 1489 93 66 Tp141 2.2 3.3 6.4 4.1 7 84 Tp145 73 76 70 82 75 77 Tp146 3.62.2 69 66 91 83 Tp149 1.4 4 40 3.5 85 40 Tp150 1.5 5.4 60 9 80 50 Tp1552.7 24 62.5 68 89 78 Tp160 18.5 34.4 32 81 84 90 Tp170 1.1 0.8 2.3 0.52.3 10 Tp175 1.9 1.2 25 3 2 33 Tp180 0.9 0.5 0 2.7 2.6 33 Tp190 1.6 32 077 90 50 Tp200 2 14 36 77 95 50 Tp210 0.8 6 11 64 91 91 Tp250 63 66 5691 84 79 Tp260 10 20 55 91 83 67

Industrial Applicability

[0106] The compounds of the present invention have retinoid actions andare useful as active ingredients of medicaments for preventive ortherapeutic treatments of vitamin A deficiency disease and agents forsuppressing action of a physiologically active substance which binds toan intranuclear receptor belonging to the intranuclear receptor superfamily to exhibit the physiological action.

What is claimed is:
 1. A compound represented by the following generalformula (I) or a salt thereof:

wherein R¹, R², R³ and R⁴ independently represent hydrogen atom, a C₁₋₁₀alkyl group (said alkyl group may be substituted), or a C₁₋₆ alkoxylgroup, and when R² and R³ are adjacent to each other, they may combinetogether with carbon atoms of the phenyl group to which R² and R³ bindto form a 5- or 6-membered ring (said ring may have one or more C₁₋₄alkyl groups or one condensed benzene ring which may have one or moresubstituents on the ring); the ring represented by Ar represents an arylring or a heteroaryl ring; X represents a single bond, —N═N—, —CON(R⁵)—(wherein R⁵ represents hydrogen atom or a C₁₋₆ alkyl group),—(C═C)_(n)CON(R⁶)— (wherein n represents an integer of 1 to 3, and R⁶represents hydrogen atom or a C₁₋₆ alkyl group), —N(R⁷)CON(R⁸)— (R⁷ andR⁸ represent hydrogen atom or a C₁₋₆ alkyl group), —SO₂N(R⁹)— (R⁹represents hydrogen atom or a C₁₋₆ alkyl group), —N(R¹⁰)— (R¹⁰represents hydrogen atom, a C₁₋₆ alkyl group, or a C₁₋₆ acyl group), aC₁₋₆ alkylene group (said alkylene group may contain one or moreunsaturated bonds or a cyclic structure), an aryldiyl group, or aheterocyclic diyl group; Y represents hydrogen atom, —OR¹¹ (R¹¹represents hydrogen atom, a C₁₋₆ alkyl group, or a C₁₋₆ acyl group),—NHR¹² (R¹² represents hydrogen atom, a C₁₋₆ alkyl group, a C₁₋₆ acylgroup, or amino group), or a halogen atom.
 2. The compound or saltthereof according to claim 1, wherein R⁴ is hydrogen atom or a C₁₋₆alkyl group, Y is hydrogen atom, hydroxyl group, a C₁₋₆ alkoxyl group,hydrazino group, or a halogen atom.
 3. A medicament comprising thecompound or the physiologically acceptable salt thereof according toclaim 1 or
 2. 4. The medicament according to claim 3, which is used asan agent for suppressing action of a physiologically active substancewhich binds to an intranuclear receptor belonging to the intranuclearreceptor super family to exhibit a physiological action.